CN107573340B - Preparation and application of 2-carbamoyl-4-arylheteropyridine compounds - Google Patents

Abstract

The invention provides 2-carbamoyl-4-heteroaromatic pyridine derivatives, and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof, wherein a substituent R₁、R₂Y has the meaning given in the description. The invention also relates to a compound with a general formula I, which has a strong effect of inhibiting c-Met kinase, and also relates to application of the compound and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparing medicines for treating diseases caused by abnormal high expression of c-Met kinase, in particular to application in preparing medicines for treating and/or preventing cancers.

Description

Preparation and application of 2-carbamoyl-4-arylheteropyridine compounds

technical field

The present invention relates to novel 2-carbamoyl-4-arylheteropyridine compounds and methods for preparing pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, and pharmaceutical compositions containing the compounds, and Use thereof in the manufacture of a medicament for the treatment and/or prevention of cancer.

Background technique

Malignant tumor is a disease that seriously endangers human health and life. The mortality rate caused by human malignant tumor is second only to cardiovascular. c-Met kinase is widely present in epithelial tissues and plays an important role in embryonic development and wound healing. c-Met is not only abnormally expressed in a variety of malignant tumors, and regulates tumor cell growth, invasion, metastasis and apoptosis, but also interacts with various membrane receptors. Studies have shown that the interaction between c-Met and membrane receptors affects the role of signaling molecules, which further affects the process of tumor invasion, metastasis and angiogenesis, resulting in the emergence of tumor drug resistance. Numerous studies have confirmed that the c-Met signaling pathway is associated with tumor drug resistance, which provides a theoretical basis for the development of multi-targeted kinase inhibitors. Receptor tyrosine kinases (RTKs) play critical roles in signal transduction pathways and cellular processes, many of which are involved in cancer. c-Met (hepatocyte growth factor/scatter factor receptor (HGF/SF)) belongs to the subfamily of RTKs consisting of an extracellular alpha chain and a transmembrane chain linked by disulfide bonds. The existence of c-Met has been demonstrated to include various possibilities, including that it is frequently amplified or overexpressed in brain, colorectal, gastric, lung, head, neck and olfactory cancers. c-Met shows high potential as a therapeutic target for human cancers.

c-Met is a protein encoded by the proto-oncogene c-Met, located on human chromosome 7 7q21-q31, with a size of more than 120kb, including 21 exons and 20 introns [4]. The protein product encoded by the c-Met gene is a single-chain precursor of 1.7×105 synthesized first, and then cleaved and rearranged into a 5×104 α subunit and a 1.4×105 β subunit, and the two subunits are connected by disulfide bonds. A 1.9 x 105 heterodimer was formed. The α subunit is located in the extracellular region, and the β subunit is divided into an extracellular region, a transmembrane region and an intracellular region. The domain includes a PTK region and an autophosphorylation site with tyrosine kinase activity. The natural ligand of c-Met is HGF, also known as diffusing factor, a multi-beta functional growth factor that promotes transformation and tumor formation by inducing mitosis and cell motility. HGF stimulates cell motility and invasion through various signaling pathways. promote tumor metastasis. After c-Met specifically binds to HGF, it induces a conformational change of c-Met protein and activates PTK in the receptor's intracellular protein kinase domain, thereby causing autophosphorylation of the receptor, followed by activation through a series of phosphorylation reactions Tyrosine phosphorylation of proteins such as phospholipases (PLCy, phosphoinositide 3-kinase (PI3K), Ras protein, Src protein, adaptor protein Gab1 and growth factor receptor binding protein (Grb2), etc. Tyrosine phosphorylation, and then the cascaded phosphorylation reaction amplifies the signal step by step, and finally transfers to the nucleus to cause a series of biological effects, regulating cell proliferation, differentiation, morphogenesis and invasion movement, etc. In addition, HGF/c- Met signaling pathway can also regulate the activation of β4 integrins, focal adhesion complexes and non-kinase binding molecules, which are closely related to the adhesion and invasion of tumor cells and the formation of tumor angiogenesis.

c-Met kinase is widely present in epithelial tissues and plays an important role in embryonic development and wound healing. Recent studies have shown that c-Met kinase has abnormally high expression in lung cancer, colon cancer, liver cancer, rectal cancer, gastric cancer, kidney cancer, ovarian cancer, glioma, melanoma, breast cancer, prostate cancer and other tumor tissues. Mutation or altered activity. c-Met kinase can promote tumor cell proliferation, regulate tumor cell migration, enhance tumor cell invasion ability and induce tumor angiogenesis. Currently, c-Met kinase has become an important target for anti-tumor drug research.

In order to develop new and efficient anti-tumor drugs, the inventors have conducted extensive research on 2-carbamoyl-4-arylheteropyridine compounds, modified and transformed multiple structural sites, and synthesized a series of novel structures. 2-carbamoyl-4-aromatic heteropyridine derivatives. In vitro anti-tumor activity screening test showed that the compounds have anti-tumor activity.

SUMMARY OF THE INVENTION

The present invention relates to 2-carbamoyl-4-arylheteropyridine compounds represented by general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.

in:

R ₁ is cyano, methyl, ethyl, n-propyl, isopropyl;

R ₂ is selected from 1 to 4 identical or different hydrogen and fluorine;

X is O, S;

Y is -Ar ₁ -Ar ₂ ;

Ar ₁ is a (C ₆ -C ₁₀ ) heteroaryl group, the heteroaryl group contains 1 heteroatom of N, Ar ₁ and Ar ₂ are combined, and optionally substituted by 1-2 identical or different R ₃ ; Ar ₂ is (C ₆ -C ₁₀ ) heteroaryl, and Ar ₂ is substituted with an aryl substituted by R ₄ in addition to being combined with Ar ₁ ;

R ₃ and R ₄ are 1-2 selected from hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, mono- or di(C ₁ -C ₆ alkyl) substituted amino, (C ₁ -C ₆ ) alkylamido, free, salt-forming, esterified and amidated carboxyl, (C ₁ -C ₆ ) Alkylsulfinyl, sulfonyl, (C ₁ -C ₆ )alkylacyl, carbamoyl, carbamoyl mono- or di(C ₁ -C ₆ alkyl) substituted, (C ₁ -C ₃ )idene Substituents of alkyldioxy.

The present invention preferably also relates to a compound of general formula I as defined below, or a racemate or optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,

R ₁ is methyl, ethyl, n-propyl;

R ₂ is F, and its substitution position is the ortho position of the carbon atom connected to X on the benzene ring;

X is O;

Y is -Ar ₁ -Ar ₂ ;

Ar ₁ is (C ₆ -C ₁₀ ) heteroaryl group is a 6-membered heteroaryl group, this heteroaryl group contains 1 N heteroatom, Ar ₁ and Ar ₂ are combined, and optionally 1-2 identical or different R ₃ substitutions; Ar ₂ is (C ₆ -C ₁₀ ) heteroaryl, and Ar ₂ is substituted with R ₄ substituted aryl in addition to being combined with Ar ₁ ;

R ₃ , R ₄ are 1-2 selected from hydrogen, halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ )alkoxy, optionally halogenated (C ₁ -C ₄ ) Alkyl or (C ₁ -C ₄ )alkoxy, mono- or bis(C ₁ -C ₆ alkyl) substituted amino, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )alkyl , (C ₁ -C ₆ )alkylacyl, carbamoyl, carbamoyl substituted with mono- or bis(C ₁ -C ₆ alkyl), (C ₁ -C ₃ )alkylenedioxy.

The present invention preferably also relates to a compound of general formula I as defined below, or a racemate or optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,

R ₁ is methyl, ethyl, n-propyl;

R ₂ is F, and its substitution position is the ortho position of the carbon atom connected to X on the benzene ring;

X is O;

Y is

R ₃ is H;

_R4 is fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl and trifluoromethoxy.

Very particularly preferred derivatives of the following general formula I of the present invention, including their racemates or optical isomers, and their pharmaceutically acceptable salts and/or hydrates, but these compounds do not imply any limitation to the present invention :

(1) N-(3-Fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide

(2) 1-(4-Chlorophenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide

(3) 1-(4-Bromophenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide

(4) N-(3-Fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-1-(4-methoxyphenyl)-2- Oxo-1,2-dihydro-1,8-naphthalene-3-carboxamide

(5) N-(3-Fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1-phenyl-1,2- Dihydro-1,8-naphthalene-3-carboxamide

(6) 1-(4-Bromo-2-fluorophenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)- 2-oxo-1,2-dihydro-1-,8-naphthyridine-3-carboxamide

(7) 1-(3-Chloro-4-fluorophenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)- 2-oxo-1,2-dihydro-1-,8-naphthyridine-3-carboxamide

(8) 1-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy )Phenyl)-2-oxo-1,2-dihydro-1,8-naphthalene-3-carboxamide

(9) 1-(4-Fluorophenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2 -Dihydro-1,8-naphthalene-3-carboxamide

(10) 1-(4-Chlorophenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2 -Dihydro-1,8-naphthalene-3-carboxamide

(11) 1-(4-Bromophenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2 -Dihydro-1,8-naphthalene-3-carboxamide

(12) 1-(4-Methoxyphenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1 ,2-Dihydro-1,8-naphthalene-3-carboxamide

(13) N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1-phenyl-1,2-dihydro-1 ,8-Naphthalene-3-carboxamide

(14) 1-(4-Bromo-2-fluorophenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide

(15) 1-(3-Chloro-4-fluorophenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide

(16) 1-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl) -2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide

(17) N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2 -Dihydro-1,8-naphthalene-3-carboxamide

(18) 1-(4-Chlorophenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2 -Dihydro-1,8-naphthalene-3-carboxamide

(19) 1-(4-Bromophenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2 -Dihydro-1,8-naphthalene-3-carboxamide

(20) N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-1-(4-methoxyphenyl)-2-oxo-1 ,2-Dihydro-1,8-naphthalene-3-carboxamide

(21) N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1-phenyl-1,2-dihydro-1 ,8-Naphthalene-3-carboxamide

(22) 1-(4-Bromo-2-fluorophenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide

(23) 1-(3-Chloro-4-fluorophenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide

(24) 1-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl) -2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide

(25) 1-(4-Fluorophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2-di Hydro-1,8-naphthalene-3-carboxamide

(26) 1-(4-Chlorophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2-di Hydro-1,8-naphthalene-3-carboxamide

(27) 1-(4-Bromophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2-di Hydro-1,8-naphthalene-3-carboxamide

(28) 1-(4-Methoxyphenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2 -Dihydro-1,8-naphthalene-3-carboxamide

(29) 2-oxo-1-phenyl-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2-dihydro-1,8 -Naphthalene-3-carboxamide

(30) 1-(4-Bromo-2-fluorophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1 ,2-Dihydro-1,8-naphthalene-3-carboxamide

(31) 1-(3-Chloro-4-fluorophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1 ,2-Dihydro-1,8-naphthalene-3-carboxamide

(32) 1-(2-Chloro-4-(trifluoromethyl)phenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy) Phenyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide

The 2-carbamoyl-4-arylheteropyridine derivatives of the general formula I of the present invention can be combined with an acid to form a pharmaceutically acceptable salt thereof according to some common methods in the art to which the present invention belongs. Acids may include inorganic or organic acids, and salts with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid , acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, tartaric acid, benzenesulfonic acid, benzoic acid or p-toluenesulfonic acid, etc. In addition, the present invention also includes prodrugs of the compounds of the present invention. According to the present invention, prodrugs are derivatives of compounds of general formula I, which themselves may have less activity or even no activity, but after administration, under physiological conditions (for example by metabolism, solvolysis or otherwise) is converted into the corresponding biologically active form.

Unless otherwise indicated, the term "halo" as used herein refers to fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "cycloalkyl" refers to substituted or unsubstituted cycloalkyl; "alkenyl" refers to straight or branched chain alkenyl; "alkynyl" refers to straight or branched chain alkynyl; "aryl" refers to the removal of one hydrogen from an aromatic hydrocarbon Atom-derived organic groups, such as phenyl, naphthyl; 5-10 membered heteroaryl groups containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group can be It is monocyclic or polycyclic, the ring system is aromatic and contains 5-10 atoms in total, such as imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, benzothienyl, Benzofuranyl, benzimidazolyl, benzothiazolyl, indolyl, quinolinyl, etc.; 5-10 membered heterocyclic groups include one or more heteroatoms selected from N, O and S, wherein each The ring system of a heteroaryl group may be monocyclic or polycyclic, but non-aromatic, and the ring system contains a total of 5-10 atoms, which may optionally include 1 or 2 carbon-carbon double bonds or carbon-carbon triple bonds. As a bond, a pyrrolidinyl group, a morpholinyl group, a piperazinyl group, a piperidinyl group, a thiazolinyl group, etc. are mentioned, for example.

The present invention also relates to the compound of general formula I which has a strong inhibitory effect on c-Met kinase, and also relates to the preparation and treatment of such compounds and their pharmaceutically acceptable salts and hydrates caused by abnormally high expression of c-Met kinase. Use in medicaments for diseases, especially in the manufacture of medicaments for the treatment and/or prevention of cancer.

Schemes 1-3 below describe the preparation of compounds of general formula I of the present invention, all starting materials were prepared by methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry, or commercially available. All final compounds of the present invention are prepared by methods described in these synthetic routes, or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variables used in these synthetic routes are as defined below or as defined in the claims.

R₃、R₄如发明内容部分所定义，均可按在路线1的方法由中间体A和中间体B通过取代反应制得。According to the compounds of formula I of the present invention, Y is

R ₃ and R ₄ are as defined in the Summary of the Invention, and can be prepared from intermediate A and intermediate B by substitution reaction according to the method in Scheme 1.

According to the compounds of formula I of the present invention, intermediate A is prepared as shown in Scheme 2, and other substituents are as defined in the claims.

中间体B的制备方法如路线3，其他取代基如权利要求中所定义。According to the compounds of formula I of the present invention, Y is

The preparation of intermediate B is as in Scheme 3, and other substituents are as defined in the claims.

Substituents R ₁ , R ₂ , R ₃ , R ₄ of all intermediates in the above three routes are as defined in the claims.

Detailed ways

The examples are intended to illustrate rather than limit the scope of the invention. The hydrogen nuclear magnetic resonance spectrum of the compound was determined by BrukerARX-400, and the mass spectrum was determined by Agilent1100LC/MSD; all reagents used were of analytical or chemical purity.

According to the general preparation method 1, the compounds of Examples 1-32 were respectively prepared (see Table 1)

Table 1 Compounds prepared in Examples 1-32

Example 1N-(3-Fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo- 1,2-Dihydro-1,8-naphthalene-3-carboxamide

ESI-MS m/z: 527.14, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (d, J=21.3 Hz, 1H), 8.66 (s, 1H), 8.54 (d, J=4.4 Hz, 1H), 8.52(d, J＝6.9Hz, 2H), 8.50(d, J＝5.4Hz, 1H), 8.15(d, J＝12.8Hz, 1H), 7.75(t, J＝19.6Hz, 1H) ,7.66(d,J=8.3Hz,1H),7.59(t,J=8.7Hz,3H),7.56(d,J=7.8Hz,1H),7.49–7.37(m,2H),7.19(d, J=2.7Hz, 1H), 2.79(d, J=4.3Hz, 3H).

Step 1: Preparation of 4-chloropyridine acid chloride (b)

In a 100 mL round-bottomed flask, picolinic acid (10 g, 0.086 mol) and NaBr (0.1 g, 0.77 mol) were successively added, and 75 mL of thionyl chloride was used for ultrasonic dissolution. After refluxing at 80 °C for 22 h, the reaction solution was concentrated, and an appropriate amount of added Toluene is ready for use. The target product was obtained as a pale yellow liquid with a yield of 98%.

Step 2: Preparation of 4-chloro-N-picolinamide (c)

In a 100mL round-bottomed flask, 30mL of tetrahydrofuran, 30% methylamine aqueous solution (10.82g, 0.37mol), and triethylamine (11.34g, 0.11mol) were successively added, stirred for 20min under ice bath conditions, and the above key intermediates were added dropwise b. After stirring for 3h under ice bath conditions, the reaction solution was added to an appropriate amount of saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and a small amount of petroleum ether was added, and a large amount of pale yellow solid was precipitated, which was obtained by suction filtration The target product in 78% yield.

Step 3: Preparation of 4-(4-aminophenoxy)-N-picoline amide (A)

First, p-aminophenol (7.13g, 0.065mol) and potassium tert-butoxide (5.86g, 0.052mol) were added to a 50mL round-bottomed flask, and 25mL of dimethyl sulfoxide was used for ultrasonic dissolution. Stir for 1 h, at the same time, add the above key intermediate c and potassium iodide (0.0089 g, 0.004 mol) to another 50 mL round-bottomed flask, dissolve with 25 mL of dimethyl sulfoxide by ultrasonic, and stir at 80 °C for 1 h. The phenol solution was added dropwise to the key intermediate c solution and stirred at 80°C for 2.5 hours, then the reaction solution was added to saturated brine and stirred for 1 hour, extracted with a large amount of ethyl acetate, the organic phase was taken, and the organic phase was washed with an appropriate amount of activated carbon and silica gel After stirring for 1 h, suction filtration, the filtrate was dried over anhydrous sodium sulfate, concentrated, and an appropriate amount of diethyl ether was added to obtain a reddish-brown solid with a yield of 56%.

Step 4: 2-Phenylamino-nicotinic acid (d)

2-Chloronicotinic acid (5.001 g, 1.575 mol), aniline (5.899 g, 0.932 mol) and glacial acetic acid (50 mL) were added to a 100 mL round-bottomed flask and sonicated for 8 min to dissolve all the reactants. Reflux at 100°C for about 4h. Cool the reaction solution to room temperature, add 100 mL of distilled water, stir rapidly, measure pH=5, adjust pH=12 with 50% KOH solution, precipitate a large amount of pale yellow solids, filter with suction, take the filtrate, select 37% HCl solution to pH =4, a large amount of white solids were precipitated, suction filtered, and the filter cake was dried to obtain 3.682 g of white powder, with a yield of 83.6%

Step 5: (2-phenylamino-pyridin-3-yl)-methanol (e)

Add 40 mL of tetrahydrofuran to a 100 mL round-bottomed flask, add lithium aluminum tetrahydrogen (1.634 g, 0.5794 mol) in batches under nitrogen protection and ice bath conditions, stir for about 15 min, and slowly drop the tetrahydrofuran solution of the key intermediate d with a burette Add to the above reaction solution, stir for 3.5h, slowly add the reaction solution to 300mL of ethyl acetate, stir for 20min, add KOH solution dropwise to PH=12, precipitate a large amount of white solid, suction filter, and dry the filtrate with anhydrous sodium sulfate, The filtrate was concentrated, an appropriate amount of petroleum ether was added, and a large amount of white solid was precipitated, which was filtered off with suction, and the filter cake was dried to obtain 3.273 g of white powder with a yield of 79.5%.

Step 6: 2-Phenylamino-pyridine-3-carbaldehyde (f)

In a 100 mL round-bottomed flask, intermediate e and pyridinium dichromate (4.100 g, 0.315 mol) were successively added, and 75 mL of dichloromethane was used for ultrasonic dissolution. Dry with anhydrous sodium sulfate, spin-evaporate the filtrate, add 50 mL of distilled water to precipitate a large amount of light yellow solid, suction filtration, and dry the filter cake to obtain 3.043 g of light yellow powder with a yield of 55.8%.

Step 7: Ethyl 2-oxo-1-phenyl-1,2-dihydro-[1,8]naphthalene-3-carboxylate (g)

In a 100 mL round-bottomed flask, intermediate f, diethyl malonate (2.653 g, 0.212 mol), and piperidine (0.542 g, 0.182 mol) were successively added, 75 mL of ethanol was added to dissolve by ultrasonic, the temperature was raised to 110 ° C, and refluxed for 34 h, Spin dry to obtain 2.764 g of pale yellow liquid with a yield of 58.6%.

Step 8: 2-oxo-1-phenyl-1,2-dihydro-[1,8]naphthalene-3-carboxylic acid (B)

Intermediate g and potassium carbonate (2.352g, 0.231mol) were added to a 100mL round-bottomed flask in turn, 30mL of distilled water and 30mL of 1.4-dioxane were added, ultrasonically dissolved, heated to 80°C, refluxed for 5h, under an ice bath The reaction solution was poured into 100 mL of distilled water, extracted with 400 mL of ethyl acetate, added dropwise with 37% HCL to pH=6, a large amount of light yellow solid was precipitated, suction filtered, and the filter cake was dried to obtain 1.524 g of light yellow powder with a yield of 82.6 %.

Step 9: N-(3-Fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide

Intermediate A (0.066 g, 0.00042 mol) and N,N-diisopropylethylamine (0.5 mL, 0.005 mol) were added to 10 mL of dichloromethane, and Intermediate B (0.25 g, 0.00063 mol) was dissolved in 10 mL of dichloromethane was added dropwise to the above-mentioned dichloromethane solution at 0° C. After the dropwise addition was completed, the solution was slowly raised to room temperature and reacted for 1-2 hours. After the completion of the reaction, add 5 mL of 5% aqueous sodium hydroxide solution, stir for half an hour, transfer to a 250 mL separatory funnel, add 25 mL of dichloromethane, wash three times with saturated aqueous sodium carbonate solution (50 mL*3), and wash once with saturated brine , and the dichloromethane was evaporated under reduced pressure to obtain 0.05 g of pale yellow solid powder with a yield of 59.24%.

According to the method of Example 1, the compounds of Examples 2 to 34 were prepared respectively.

Example 2

1-(4-Chlorophenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1, 2-Dihydro-1,8-naphthalene-3-carboxamide

ESI-MS m/z: 543.11

Example 3

1-(4-Bromophenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1, 2-Dihydro-1,8-naphthalene-3-carboxamide

ESI-MS m/z: 587.06

Example 4

N-(3-Fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-1-(4-methoxyphenyl)-2-oxo- 1,2-Dihydro-1,8-naphthalene-3-carboxamide

ESI-MS m/z: 539.16

Example 5

N-(3-Fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1-phenyl-1,2-dihydro- 1,8-Naphthalene-3-carboxamide

ESI-MS m/z: 509.15, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.68 (d, J=20.3 Hz, 1H), 9.18 (s, 1H), 8.79 (d, J=4.4 Hz, 1H), 8.62(d, J＝6.9Hz, 2H), 8.53(d, J＝5.4Hz, 1H), 8.05(d, J＝12.6Hz, 1H), 7.85(t, J＝19.4Hz, 1H) ,7.68(d,J＝8.3Hz,1H),7.58(t,J＝8.1Hz,3H),7.50(d,J＝7.5Hz,1H),7.47–7.36(m,3H),7.19(d, J=2.7Hz, 1H), 2.79(d, J=4.3Hz, 3H).

Example 6

1-(4-Bromo-2-fluorophenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo Substituted-1,2-dihydro-1-,8-naphthyridine-3-carboxamide

ESI-MS m/z: 606.05, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.85 (d, J=20.6 Hz, 1H), 9.20 (s, 1H), 8.86 (s, 1H), 8.68– 8.69(m, 3H), 8.28(d, J=18.8Hz, 1H), 8.10(d, J=8.6Hz, 1H), 7.80(d, J=12.0Hz, 1H), 7.85(s, 1H), 7.67(s, 1H), 7.69(s, 1H), 7.41(d, J=9.4Hz, 1H), 7.39(s, 1H), 7.25(s, 1H), 2.88(d, J=4.7Hz, 3H) ).

Example 7

1-(3-Chloro-4-fluorophenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo Substituted-1,2-dihydro-1-,8-naphthyridine-3-carboxamide

ESI-MS m/z: 561.93, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.81 (d, J=20.3 Hz, 1H), 9.17 (s, 1H), 8.81 (s, 1H), 8.68– 8.49(m, 3H), 8.08(d, J=18.8Hz, 1H), 8.00(d, J=8.9Hz, 1H), 7.90(d, J=12.0Hz, 1H), 7.84(s, 1H), 7.61(s, 1H), 7.49(s, 1H), 7.43(d, J=9.1Hz, 1H), 7.39(s, 1H), 7.21(s, 1H), 2.78(d, J=4.6Hz, 3H) ).

Example 8

1-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl )-2-oxo-1,2-dihydro-1,8-naphthalene-3-carboxamide

ESI-MS m/z: 661.10

Example 9

1-(4-Fluorophenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2-dihydro -1,8-Naphthalene-3-carboxamide

ESI-MS m/z: 509.15

Example 10

1-(4-Chlorophenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2-dihydro -1,8-Naphthalene-3-carboxamide

ESI-MS m/z: 525.12

Example 11

1-(4-Bromophenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2-dihydro -1,8-Naphthalene-3-carboxamide

ESI-MS m/z: 569.17

Example 12

1-(4-Methoxyphenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2- Dihydro-1,8-naphthalene-3-carboxamide

ESI-MS m/z: 521.53

Example 13

N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1-phenyl-1,2-dihydro-1,8- Naphthalene-3-carboxamide

ESI-MS m/z: 491.16

Example 14

N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl )-1-(4-Methoxyphenyl)-2-oxo-1,2-dihydro-1,8-naphthalene-3-carboxamide

ESI-MS m/z: 587.06

Example 15

1-(3-Chloro-4-fluorophenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1, 2-Dihydro-1,8-naphthalene-3-carboxamide

ESI-MS m/z: 543.11

Example 16

1-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2- Oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide

ESI-MS m/z: 593.11

Example 17

N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydro -1,8-Naphthalene-3-carboxamide

ESI-MS m/z: 523.17

Example 18

1-(4-Chlorophenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2-dihydro -1,8-Naphthalene-3-carboxamide

ESI-MS m/z: 539.14

Example 19

1-(4-Bromophenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2-dihydro -1,8-Naphthalene-3-carboxamide

ESI-MS m/z: 583.09

Example 20

N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-1-(4-methoxyphenyl)-2-oxo-1,2- Dihydro-1,8-naphthalene-3-carboxamide

ESI-MS m/z: 535.19

Example 21

N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1-phenyl-1,2-dihydro-1,8- Naphthalene-3-carboxamide

ESI-MS m/z: 505.18

Example 22

1-(4-Bromo-2-fluorophenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1, 2-Dihydro-1,8-naphthalene-3-carboxamide

ESI-MS m/z: 601.18

Example 23

1-(3-Chloro-4-fluorophenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1, 2-Dihydro-1,8-naphthalene-3-carboxamide

ESI-MS m/z: 571.13

Example 24

1-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2- Oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide

ESI-MS m/z: 607.12

Example 25

1-(4-Fluorophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2-dihydro-1 ,8-Naphthalene-3-carboxamide

ESI-MS m/z: 537.18, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.80 (s, 1H), 9.17 (s, 1H), 8.79 (t, J=6.1 Hz, 1H), 8.60 ( d,J＝5.6Hz,2H),8.52(d,J＝5.6Hz,1H),7.95(s,1H),7.89(d,J＝8.9Hz,2H),7.46(dd,J＝11.8,6.7 Hz, 3H), 7.42–7.39 (m, 2H), 7.25 (d, J=8.9Hz, 2H), 7.17 (dd, J=5.6, 2.5Hz, 1H), 3.24–3.18 (m, 2H), 1.51 (dd,J=14.5,7.2Hz,2H),0.84(t,J=7.4Hz,3H).

Example 26

1-(4-Chlorophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2-dihydro-1 ,8-Naphthalene-3-carboxamide

ESI-MS m/z: 553.15

Example 27

1-(4-Bromophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2-dihydro-1 ,8-Naphthalene-3-carboxamide

ESI-MS m/z: 598.46

Example 28

1-(4-Methoxyphenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2-dihydro -1,8-Naphthalene-3-carboxamide

ESI-MS m/z: 549.20

Example 29

1-(4-Methoxyphenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2-dihydro -1,8-Naphthalene-3-carboxamide

ESI-MS m/z: 519.19

Example 30

1-(4-Bromo-2-fluorophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2- Dihydro-1,8-naphthalene-3-carboxamide

ESI-MS m/z: 615.09

Example 31

1-(3-Chloro-4-fluorophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2- Dihydro-1,8-naphthalene-3-carboxamide

ESI-MS m/z: 571.14

Example 32

1-(2-Chloro-4-(trifluoromethyl)phenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl) -1,2-Dihydro-1,8-naphthyridine-3-carboxamide

ESI-MS m/z: 621.14

In vitro antitumor cell activity

In vitro inhibition of lung cancer cells H460, colon cancer cells HT-29, human gastric cancer cells MKN-45, and lung adenocarcinoma cells was carried out on the 2-carbamoyl-4-arylheteropyridine derivatives containing the above formula I according to the present invention. Activity screening of A549 and bladder cancer cells U-87MG.

(1) After the cells were recovered and passaged 2-3 times to stabilize, they were digested from the bottom of the culture flask with trypsin solution (0.25%). After the cell digestion solution was poured into the centrifuge tube, the culture solution was added to stop the digestion. Centrifuge the centrifuge tube at 800 r/min for 10 min, discard the supernatant, add 5 mL of culture medium, mix the cells by pipetting, pipette 10 μL of the cell suspension and add it to a cell counting plate for counting, and adjust the cell concentration to 10 ⁴ cells/well. In the 96-well plate, 100 μL of cell suspension was added to the rest of the 96-well plates, except that A1 was a blank well without cells. The 96-well plate was placed in an incubator for 24 h.

(2) Dissolve the test sample with 50 μL dimethyl sulfoxide, then add an appropriate amount of culture medium to dissolve the sample into 2 mg/mL liquid, and then dilute the sample to 20, 4, 0.8, 0.16 in a 24-well plate, 0.032 μg/mL.

Each concentration was added to 3 wells, and the growth of the cells in the surrounding two rows and two columns was greatly affected by the environment, and was only used for the blank cell wells. The 96-well plate was placed in an incubator for 72 h.

(3) Discard the medicated culture medium in the 96-well plate, wash the cells twice with phosphate buffered solution (PBS), add 100 μL of MTT (tetrazolium) (0.5 mg/mL) to each well and put it into the incubator After 4 h, the MTT solution was discarded, and 100 μL of dimethyl sulfoxide was added. Shake on a magnetic shaker to fully dissolve the surviving cells and the MTT reaction product formazan, and put it into a microplate reader to measure the results. The drug IC ₅₀ value can be obtained by the BLiss method.

The compounds inhibited the activity of lung cancer cells H460, colon cancer cells HT-29, human gastric cancer cells MKN-45, lung adenocarcinoma cells A549 and bladder cancer cells U-87MG (see Table 2).

c-Met enzyme activity assay

The assay used to measure c-Met kinase activity is based on an enzyme-linked immunosorbent assay (ELISA). The specific operations are:

Example compounds, 50 pMc-Met (His-tagged recombinant human Met (amino acid 974-terminal), expressed by baculovirus and 5 μM ATP in assay buffer ( 25 mM MOPS, pH 7.4, ₅ mM MgCL2, 0.5 _raMMnCL2 , 100 μM sodium orthovanadate, 0.01% TritonX-100, 1 mM DTT, final DMSO concentration 1% (v/v)) for 20 min. The reaction mixture was removed by rinsing and treated with 0.2 Phosphotyrosine-specific monoclonal antibody (PY20) conjugated to horseradish peroxidase (HRP) at μg/mL detects phosphorylated polymer substrates. After color development is stopped by the addition of 1 M phosphoric acid, spectrophotometry is performed at 450 nm. The color of the chromogenic substrate (TMB) was quantified. Inhibition data of the example compounds against c-Met kinase (see Table II).

Table 2 In vitro antitumor cell activity and c-Met enzyme activity test results

It can be clearly seen from the above test results that the compound of general formula I to be protected by the present invention has good antitumor activity in vitro, which is equivalent to or better than the marketed antitumor drug cisplatin.

While the invention has been described in terms of specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Application Example 1: Tablets

Using 10 g of the compound of Example 3, adding 20 g of auxiliary materials according to the general tableting method of pharmacy, and mixing, then compressed into 100 tablets, each weighing 300 mg.

Application Example 2: Capsules

With 10 g of the compound of Example 10, after mixing 20 g of the auxiliary material according to the requirements of pharmaceutical capsules, it was put into hollow capsules, and each capsule weighed 300 mg.

Application Example 3: Injection

Using 10 g of the compound of Example 12, according to the conventional method of pharmacy, activated carbon adsorption was carried out, filtered through a 0.65 μm microporous membrane, and filled into a nitrogen tank to prepare a water injection preparation, each filled with 2 mL, and a total of 100 bottles were filled.

Application Example 4: Aerosol

Take 10 g of the compound of Example 20, dissolve it with an appropriate amount of propylene glycol, add distilled water and other materials, and prepare a 500 mL clear solution.

Application Example 5: Suppositories

Take 10 g of the compound of Example 19, grind it finely and add an appropriate amount of glycerin, grind it evenly, add melted glycerin gelatin, grind evenly, pour it into a mold coated with lubricant, and prepare 50 suppositories.

Application example 6: film agent

With 10 g of the compound of Example 26, polyvinyl alcohol, medicinal glycerin, water, etc. were stirred and expanded, heated and dissolved, filtered through an 80-mesh sieve, and then the compound of Example 18 was added to the filtrate, stirred and dissolved, and 100 membranes were coated.

Application Example 7: Dropping Pills

10 g of the compound of Example 18 was heated, melted and mixed with 50 g of a matrix such as gelatin, and then dropped into the low-temperature liquid paraffin to obtain 1000 dropping pills.

Application Example 8: External liniment

10 g of the compound of Example 12 was mixed and ground with 2.5 g of auxiliary materials such as emulsifiers according to conventional pharmaceutical methods, and then distilled water was added to make 200 mL.

Application Example 9: Ointment

The compound 10g of Example 22 was ground into a fine powder and mixed with 500g of oily base such as vaseline.

While the invention has been described in terms of specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims (6)

1. a 2-carbamoyl-4-aromatic heteropyridine compound, is characterized in that: comprise the compound of general formula I,

in: R ₁ is methyl, ethyl, n-propyl; R ₂ is F, and its substitution position is the ortho position of the carbon atom connected to X on the benzene ring; X is O; Y is

R ₃ is H; R ₄ is fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl. 2. a kind of 2-carbamoyl-4-aromatic heteropyridine compound as claimed in claim 1 is characterized in that: comprise following compound: (1) N-(3-Fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide (2) 1-(4-Chlorophenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide (3) 1-(4-Bromophenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide (4) N-(3-Fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-1-(4-methoxyphenyl)-2- Oxo-1,2-dihydro-1,8-naphthalene-3-carboxamide (5) N-(3-Fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1-phenyl-1,2- Dihydro-1,8-naphthalene-3-carboxamide (6) 1-(4-Bromo-2-fluorophenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)- 2-oxo-1,2-dihydro-1-,8-naphthyridine-3-carboxamide (7) 1-(3-Chloro-4-fluorophenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)- 2-oxo-1,2-dihydro-1-,8-naphthyridine-3-carboxamide (8) 1-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(3-fluoro-4-((2-(methylcarbamoyl)pyridin-4-yl)oxy )Phenyl)-2-oxo-1,2-dihydro-1,8-naphthalene-3-carboxamide (9) 1-(4-Fluorophenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2 -Dihydro-1,8-naphthalene-3-carboxamide (10) 1-(4-Chlorophenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2 -Dihydro-1,8-naphthalene-3-carboxamide (11) 1-(4-Bromophenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2 -Dihydro-1,8-naphthalene-3-carboxamide (12) 1-(4-Methoxyphenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1 ,2-Dihydro-1,8-naphthalene-3-carboxamide (13) N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1-phenyl-1,2-dihydro-1 ,8-Naphthalene-3-carboxamide (14) 1-(4-Bromo-2-fluorophenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide (15) 1-(3-Chloro-4-fluorophenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide (16) 1-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl) -2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (17) N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2 -Dihydro-1,8-naphthalene-3-carboxamide (18) 1-(4-Chlorophenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2 -Dihydro-1,8-naphthalene-3-carboxamide (19) 1-(4-Bromophenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1,2 -Dihydro-1,8-naphthalene-3-carboxamide (20) N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-1-(4-methoxyphenyl)-2-oxo-1 ,2-Dihydro-1,8-naphthalene-3-carboxamide (21) N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo-1-phenyl-1,2-dihydro-1 ,8-Naphthalene-3-carboxamide (22) 1-(4-Bromo-2-fluorophenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide (23) 1-(3-Chloro-4-fluorophenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-2-oxo -1,2-Dihydro-1,8-naphthalene-3-carboxamide (24) 1-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl) -2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (25) 1-(4-Fluorophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2-di Hydro-1,8-naphthalene-3-carboxamide (26) 1-(4-Chlorophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2-di Hydro-1,8-naphthalene-3-carboxamide (27) 1-(4-Bromophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2-di Hydro-1,8-naphthalene-3-carboxamide (28) 1-(4-Methoxyphenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2 -Dihydro-1,8-naphthalene-3-carboxamide (29) 2-oxo-1-phenyl-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1,2-dihydro-1,8 -Naphthalene-3-carboxamide (30) 1-(4-Bromo-2-fluorophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1 ,2-Dihydro-1,8-naphthalene-3-carboxamide (31) 1-(3-Chloro-4-fluorophenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy)phenyl)-1 ,2-Dihydro-1,8-naphthalene-3-carboxamide (32) 1-(2-Chloro-4-(trifluoromethyl)phenyl)-2-oxo-N-(4-((2-(propylamino)pyridin-4-yl)oxy) phenyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide. 3. A pharmaceutical composition comprising a compound of any one of claims 1-2 as an active ingredient and a pharmaceutically acceptable excipient. 4. Use of the compound of any one of claims 1-2 in the preparation of a medicament for the treatment and/or prevention of proliferative diseases. 5. Use of a compound of any one of claims 1-2 for the manufacture of a medicament for the treatment and/or prevention of cancer. 6. Use of the compound of any one of claims 1-2 in the preparation of a medicament for the treatment and/or prevention of lung cancer, liver cancer, gastric cancer, colon cancer, and breast cancer.